The objective of this proposal is to study the neurochemical alterations that occur in a rat model of human methamphetamine (METH) abuse. Our laboratory has developed a treatment protocol which simulates aspects of human METH abuse that have been overlooked in many of the treatment patterns in the literature, as well as previously in our own lab. Our inclusion of an escalating dose phase of exposure to METH will simulate the typical ?recreational use? period that precedes high-dose patterns of METH abuse in humans, and will likely result in neuroadaptations which are protective against subsequent high-dose administration. One aspect of this proposal is to characterize those adaptations in rats. An additional factor taken into consideration in our proposed treatment protocol is the difference in half-life of METH elimination in rats and humans. We have incorporated into our protocol an increased frequency of administration in order to compensate for the faster elimination of METH in rats. As a result, the duration of exposure and the profile of plasma drug accumulation with multiple doses will closely simulate those predicted to occur in human abusers. Therefore, the neurochemical alterations that we will characterize which result from an escalating dose exposure + a binge (administrations every 15 min for 10 h) will more likely be reflective of similar alterations in human METH abusers.